U.S. patent number 4,256,743 [Application Number 06/088,397] was granted by the patent office on 1981-03-17 for inhibition of bone resorption with h.sub.1 -blocking antihistamines.
This patent grant is currently assigned to President and Fellows of Harvard College. Invention is credited to Paul Goldhaber.
United States Patent |
4,256,743 |
Goldhaber |
March 17, 1981 |
Inhibition of bone resorption with H.sub.1 -blocking
antihistamines
Abstract
Inhibition of bone resorption in mammals suffering from a
disease in which bone resorption exceeds new bone formation by
administering an H.sub.1 -blocking antihistamine.
Inventors: |
Goldhaber; Paul (Waban,
MA) |
Assignee: |
President and Fellows of Harvard
College (Cambridge, MA)
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Family
ID: |
26685615 |
Appl.
No.: |
06/088,397 |
Filed: |
October 26, 1979 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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14070 |
Feb 22, 1979 |
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Current U.S.
Class: |
514/226.2;
514/352; 514/900 |
Current CPC
Class: |
A61K
31/54 (20130101); A61K 31/44 (20130101); Y10S
514/90 (20130101) |
Current International
Class: |
A61K
31/44 (20060101); A61K 31/54 (20060101); A61K
031/44 (); A61K 031/54 (); A61K 031/13 () |
Field of
Search: |
;424/263,246,247,325 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Inter. Symp. on Osteoporosis-1st-N.Y. (1969)-Osteoporosis
(1970)-pp. 174-186, Raisz. .
Clin. Exp. Immunol. (1978) 33, 166-173-Wennstrom et al. .
J. Dent. Res. 45, 490-499 (1966)-Goldhaber. .
J. Dent. Res. 50, 278-285 (1971)-Goldhaber. .
57th Amer. Meeting Int. Assoc. Dent. Res. Prog. Abst. (Mar. 1979).
.
56th Amer. Meeting Int. Assoc. Dent. Res. Prog. Abst. (Mar.
1978)..
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Primary Examiner: Robinson; Douglas W.
Government Interests
The invention described herein was made in the course of work under
a grant from the Department of Health, Education, and Welfare.
Parent Case Text
This application is a continuation-in part-of application Ser. No.
14,070, filed Feb. 22, 1979, now abandoned.
Claims
What is claimed is:
1. A method for inhibiting bone resorption which comprises
administering orally to a mammal suffering from osteoporosis or
chronic destructive periodontal disease an H.sub.1 -blocking
antihistamine selected from the group consisting of the H.sub.1
-blocking phenothiazines, the H.sub.1 -blocking ethylenediamines,
and the H.sub.1 -blocking indenes, the amount being from 25-50
mg/day in the case of said phenothiazines, 25-50 mg up to 4 times a
day in the case of said ethylenediamines, 1-2 mg 1 to 3 times a day
in the case of said indenes.
2. The method as claimed in claim 1 in which said H.sub.1 -blocking
phenothiazine is promethazine hydrochloride, said H.sub.1 -blocking
ethylenediamine is selected from the group consisting of
tripelennamine hydrochloride and pyrilamine maleate, and said
H.sub.1 -blocking indene is dimethindene maleate.
3. The method as claimed in claim 2 in which said disease is
osteoporosis and said antihistamine is promethazine
hydrochloride.
4. The method as claimed in claim 2 in which said disease is
osteoporosis and said antihistamine is tripellenamine
hydrochloride.
5. The method as claimed in claim 2 in which said disease is
osteoporosis and said antihistamine is pyrilamine maleate.
6. The method as claimed in claim 2 in which said disease is
osteoporosis and said antihistamine is dimethindene maleate.
7. The method as claimed in claim 2 in which said disease is
periodontitis and said antihistamine is promethazine
hydrochloride.
8. The method as claimed in claim 2 in which said disease is
periodontitis and said antihistamine is tripellenamine
hydrochloride.
9. The method as claimed in claim 2 in which said disease is
periodontitis and said antihistamine is pyrilamine maleate.
10. The method as claimed in claim 2 in which said disease is
periodontitis and said antihistamine is dimethindene maleate.
11. The method as claimed in claim 1 in which said H.sub.1
-blocking antihistamine is an H.sub.1 -blocking phenothiazine.
12. The method as claimed in claim 1 in which said H.sub.1
-blocking antihistamine is an H.sub.1 -blocking
ethylenediamine.
13. The method as claimed in claim 1 in which said H.sub.1
-blocking antihistamine is an H.sub.1 -blocking indene.
Description
This invention relates to a method for inhibiting bone resorption
in mammals by administering an effective amount of H.sub.1
-blocking antihistamine.
The osteolytic diseases are characterized by rates of bone
resorption which are significantly higher than the rates of new
bone formation. One disease in which this occurs is chronic
destructive periodontal disease (periodontitis); patients suffer
gradual erosion of the jaw bone around the roots of the teeth,
leading to loosening of the teeth and eventual exfoliation or
extraction. Patients suffering from another resorption disease
osteoporosis, may experience a loss of bone substance so severe
that their bones cannot withstand ordinary mechanical stress, and
thus are susceptible to fracture during normal function.
Several methods of treating bone resorption diseases are in use,
but none is entirely satisfactory. Known treatments include
administering sodium fluoride, calcium compounds, calcitonin, or
estrogens.
The method of the present invention can be applied to any mammal
suffering from any of the bone resorption diseases characterized by
a rate of bone resorption which exceeds the rate of new bone
formation. The method comprises administering to a mammal,
including a human, suffering from such a disease, an effective
amount of any of the H.sub.1 -blocking antihistamines orally.
H.sub.1 -blocking antihistamines have been used for a number of
years to treat allergic diseases but their therapeutic
effectiveness in treating bone diseases has been unknown. However,
as disclosed in the present invention, it has been discovered that
administering the H.sub.1 -blocking antihistamines effectively
inhibits bone resorption. These agents have the additional
advantage of causing minimal and easily avoided side effects. The
inhibitory effect of these agents is at present most advantageously
demonstrated in tissue culture in which bone resorption has been
stimulated by the addition of parathyroid extract. Of the agents
herein described, a phenothiazine such as promethazine
hydrochloride, which is an H.sub.1 -blocking antihistamine, is one
of the most effective. The phenothiazines which are not H.sub.1
-blocking antihistamines are not part of the present invention.
Other classes of H.sub.1 -blocking antihistamines which, according
to the method of the present invention, are effective in inhibiting
bone resorption include the ethylenediamines, of which
tripelennamine hydrochloride and pyrilamine maleate are examples,
and the indenes, of which dimethindene maleate is an example.
The following specific example is intended to illustrate more fully
the nature of the present invention without acting as a limitation
upon its scope.
EXAMPLE
Bone tissue culture systems are prepared according to the method
described in Goldhaber, J. Dent. Res. 45:490-499 (1966) and
Goldhaber, J. Dent. Res. 50:278-285 (1971). Each tissue sample, in
a Leighton tube, is grown in Medium 1, which supports only bone
resorption, or in Medium 2, which supports both bone resorption and
new bone (osteoid) formation. Medium 1 consists of heated horse
serum and Gey's balanced salt solution in the ratio 6:4. In
addition, the medium contains 100 units of penicillin, 100
micrograms of streptomycin, 10 units of heparin, and 0.1 units of
parathyroid extract per ml of medium. Medium 2 contains heated
horse serum, 13-day chicken embryo extract and Gey's balanced salt
solution in the ratio 2:2:6, and antibiotics as described above.
Water-soluble test compounds are added to the balanced salt
solution portion of the media; lipid-soluble compounds are
dissolved first in a small amount of absolute ethanol and then
added to the complete medium. Each tube receives 2 ml of the
appropriate medium and is gassed briefly with a mixture of 50%
O.sub.2 and 50% N.sub.2, stoppered, and placed horizontally in a
roller drum at 37.degree. C. Every 2-3 days the used media are
replaced with fresh media and the tubes are regassed.
Microscopic observations are made every 2 or 3 days on the living
cultures (four tubes per group) and each culture is scored for the
extent of bone resorption present. The amount and condition of the
cellular outgrowth from the margins of the cultured bone is noted.
The used supernatant fluids from cultures maintained in Medium 1
are collected at each "feeding" (2-3 days) and analyzed for calcium
content with a Corning Calcium Analyzer, Model 940. Cultures
prepared in Medium 1 are maintained for 1 week, whereas those
prepared in Medium 2 are maintained for 2 weeks. Upon termination
of the experiment, the calvaria are fixed, sectioned, and stained
with hematoxylin and eosin. In all experiments, the last score
obtained by microscopic observation of each living culture is
expressed as the percentage resorption of the total calvarium.
These data are averaged per group. Resorption scores determined
morphologically correlate to a highly significant degree with the
chemical determination of total calcium released into the medium
during the course of the experiment. Both sets of data are
subjected to statistical evaluation (analysis of variance).
Sections of calvaria stained with hematoxylin and eosin are
examined for cell viability in all cultures and for the presence of
newly formed osteoid in cultures that were maintained in Medium
2.
Table I, column 2 below shows the generic name of the compounds
that inhibit bone resorption. Column 3 shows their chemical
formulae, whereas columns 4, 5, and 6 show the dose ranges tested
in culture, the nontoxic dose ranges inhibiting parathyroid
extract-stimulated bone resorption and the selective dose ranges in
the remodeling system, respectively. Column 7 shows the adult human
oral dose for each compound to achieve inhibition of bone
resorption.
TABLE 1
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H.sub.1 -Blocking Antihistamines Inhibitory to Bone Resorption in
Tissue Culture 5 4 Nontoxic dose 6 Dose Range of range inhibiting
Selective dose 7 2 3 concentrations parathyroid range in Daily
adult 1 Generic Chemical tested in extract-stimulated remodeling
human oral Class name formula tissue culture bone resportion*
system** dose
__________________________________________________________________________
Promethazine Phenothiazines Hydrochloride C.sub.17 H.sub.20 N.sub.2
S . HCl 1-100 .mu.g/ml 10-25 .mu.g/ml 5-25 .mu.g/ml 25-50 mg/day
Ethylenediamines Tripelennamine Hydrochloride C.sub.16 H.sub.21
N.sub.3 . HCl 10-50 .mu.g/ml 20-40 .mu.g/ml 10-50 .mu.g/ml 25-50 mg
up to 4 X/day Pyrilamine Maleate C.sub.17 H.sub.23 N.sub.3 0 .
C.sub.4 H.sub.4 O.sub.4 10-100 .mu.g/ml 30-50 .mu.g/ml 10-100
.mu.g/ml Indenes Dimethindene 1-2 mg Maleate C.sub.20 H.sub.24
N.sub.2 . C.sub.4 H.sub.4 O.sub.4 10-100 .mu.g/ml 20-50 .mu.g/ml
10-50 .mu.g/ml 1-3
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X/day *Parathyroid extract (E. Lilly & Co.), 0.1 .mu./ml, which
usually destroy 60-80% of the calvarium within the 7day test
period. **Dose range wherein bone resorption is inhibited to a
greater extent tha new osteoid formation is inhibited over the
14day test period.
The active agent can be administered in pure form or in the form of
its nontoxic acid addition salts or in combination of either of
these with any conventional pharmaceutically acceptable nontoxic
carrier or vehicle.
* * * * *